I. Field of the Invention
This invention relates to regulation of cell signaling, cell growth and particularly to the regulation of cancer or cell growth.
II. Description of Related Art
The MUC1 heterodimeric mucin-type glycoprotein is expressed on the apical borders of secretory epithelial cells (Kufe et al. (1984) Hybridoma 3: 223-232). With transformation and loss of polarity, MUC1 is expressed at high levels over the entire cell membrane and in the cytoplasm (Kufe et al. (1984) Hybridoma 3: 223-232). The MUC1 N-terminal ectodomain, which consists of variable numbers of 20 amino acid tandem repeats that are extensively modified by O-linked glycans, is tethered to the cell surface through a complex with the MUC1 C-terminal transmembrane subunit (MUC1-C) (Siddiqui et al. (1988) Proc. Natl. Acad. Sci. USA 85: 2320-2323; Gendler et al. (1988) J. Biol. Chem. 263: 12820-12823; and Merlo et al. (1989) Cancer Res. 49: 6966-6971). MUC1-C integrates receptor tyrosine kinase signaling with the Wnt pathway (Li et al. (1998) Mol. Cell. Biol. 18: 7216-7224; Li et al. (2001) J. Biol. Chem. 276: 35239-35242; and Li et al. (2001) J. Biol. Chem. 276: 6061-6064). MUC1-C is also targeted to mitochondria and to the nucleus, where it contributes to the regulation of β-catenin/Tcf- and p53-mediated gene transcription (Ren et al. (2004) Cancer Cell 5: 163-175; Huang et al. (2003) Cancer Biol. Ther. 2: 702-706; and Wei et al. (2005) Cancer Cell 7: 167-178). Overexpression of MUC1 is sufficient to induce transformation and to attenuate apoptosis in the response of cells to oxidative and genotoxic stress (Ren et al. (2004) Cancer Cell 5: 163-175; Huang et al. (2003) Cancer Biol. Ther. 2: 702-706; Li et al. (2003) Oncogene 22: 6107-6110; Raina et al. (2004) J. Biol. Chem. 279: 20607-20612; and Yin et al. (2004) J. Biol. Chem. 279: 45721-45727).
The p53 transcription factor (or “p53”) is of key importance in the protection of an organism against carcinogenesis. p53 performs this function by regulating several cellular processes, the most important of which are apoptosis and cell-cycle progression. The p53 transcription factor is a nuclear phosphoprotein involved in the control of cell proliferation, and mutations in the p53 gene are commonly found to be associated with diverse type of human cancer (Levine et al. (1991) Nature 351: 453).